Synthesis of a-norandrostane steroids



United States Patent '0 SYNTHESIS OF A-NORANDROSTANE STEROIDS Seymour D.Levine, North Brunswick, and Patrick A. Diassi, Westfield, N.J.,assignors to E. R. Squibb & Sons, Inc., New York, N.Y., a corporation ofDelaware No Drawing. Continuation-impart of applications Ser. No.383,243, July 16, 1964, and Ser. No. 407,515, Oct. 29, 1964. ,Thisapplication Oct. 26, 1966, Ser. No. 589,497

Int. Cl. C07d 101/00; C07c 171/06; A61k 27/00 US. Cl. 260-3433 16 ClaimsABSTRACT OF THE DISCLOSURE Disclosed herein are A-norandrostanecompounds of the formula wherein each R and R is hydrogen and together Rand R is 0x0 (0 R" is selected from the group c0nsist-' ing of hydroxyand acyloxy, wherein the acyl radical is of a straight chain saturatedhydrocarbon carboxylic acid of up to 12 carbon atoms; X is selected fromthe group consisting of hydrogen, lower alkyl, lower alkenyl and loweralkynyl; and together X and R" is oxo, H being a-bonded when R and R isoxo. These compounds have utility as anti-androgenic agents.

' lar compound and the requirements of the patient.

3,483,223 Patented Dec. 9, 1969 R 7 IEZ at wherein each R and R arehydrogen and together R and R' is oxo (0 X is selected from the groupconsisting of hydrogen, lower alkyl, lower alkenyl and lower alkynyl;and R" is selected from the group consisting of hydroxy and acyloxy antitogether X and R is oxo, H being a-bonded when R and R is oxo.

The acyl radicals preferred in the operation of this invention are thoseof hydrocarbon carboxylic acids of up to twelve carbon atoms asexemplified by the alkanoic acids (e.g., lower alkanoic acids such asacetic, propionic, butyric, and tert-pentanoic acid as Well as suchacids as octanoic acid and dodecanoic acid), the alkenoic acids, thealkynoic acids, the monocyclic aryl carboxylic acids (e.g., benzoic andtoluic acid), the monocyclic aryl lower alkanoic acids (e.g., phenaceticand fi-phenylpropionic acid), the cycloalkane carboxylic acids and thecycloalkene carboxylic acids.

Particularly preferred compounds of this invention comprise thosewherein X is hydrogen, lower alkyl, vinyl or ethynyl.

[In this application and in the appended claims, wheneverin the formulaeset forth herein a curved line (I) is employed in the linkage of atoms,it is meant to denote that the connected atom may be either in the alphaor beta position, as is determined in the respective compounds involved]The final products of this invention are physiologically active steroidsand possess anti-androgenic activity, i.e., they inhibit the action ofandrogens. The final products of this invention may be used in thetreatment of such conditions as hyperandrogenic acne and they may beformulated for such administration, the concentration and/or dosagebeing based on the activity of the particu- Ihe compounds of the instantinvention may be prepared by the processes of this invention beginningwith A-nortestosterone as starting material. The processes of thisinvention may be represented by the following equations, wherein the Acrepresents acyl and X is as hereinabove defined.

In the first step of the processes of this invention, A- nortestosteroneis oxidized, as by treatment with osmium tetroxide to yield theA-nor-2-one-3fl,5fi,17,8-triol derivative (Compound II). Compound (II)may also be prepared according to the procedures set forth in copendingapplication, Ser. No. 359,417, filed Apr. 13, 1964 now US. Patent No.3,324,171, in the names of Seymour D. Levine and Patrick A. Diassi.

Compound (II) may then be further oxidized as by treatment with periodicacid to yield the 3-0xa-5/3-hydroxy A nor 2 one derivative (CompoundIII). Compound (III) may also be prepared according to the teachings ofWeisenborn et al. in 76 JACS 552 (1954).

Compound (III) may then be treated with an alkali borohydride, forexample, sodium borohydride to yield 2,5-secobisnorandrostane diol acidderivative (Compound IV).

Compound (IV) may then be treated with an alkali metal acylate, forexample, sodium acetate, and an acylating agent, for example, an acylanhydride such as acetic anhydride, or an acyl halide, such as acetylchloride, to yield the 3-OX21-5ot-A-110I-2-0116 derivative (Compound V).

Compound (V) may then be treated with a reducing agent, for example,lithium aluminum hydride to yield the 2,5 seco 3,4 bisnorandrostane258,175 tIiol derivative (Compound VI).

Alternatively, Compound (III) may be treated directly with a reducingagent such as lithium aluminum hydride to produce a mixture of the2,5-seco-3,4-bisnorandrostane 2,55,17 8 triol (Compound VI) and the2,5-seco- 3,4-bisnorandrostane-2,5a,17,8-triol (Compound VIa), whichcompounds, if desired, may easily be acylated to the correspondingtriacetate derivatives.

Compound (VI) may be reacted, as with toluenesulfonyl chloride inpyridene to yield the 3-oxa-5u-A-norandrostane derivative (CompoundVII).

Compound (VIa) may be selectively converted to the3-oxa-5B-A-norandrostane derivative (Compound VIIa) by treatment of theabove mixture with perchloric acid in acetone.

Compounds (VII) and (VIIa) may then be treated with chromium trioxide inacetone to produce the corresponding 5w and 5fi-17-keto denatives(Compounds VIII and VIIIa).

Compounds (VIII) and (VIIIa) may be converted to the corresponding 5mand 5/i-17a-alky1-175-hydroxy derivatives (Compounds D( and IXa) bytreatment with a Grignard reagent of the formula R-Mg (halo), wherein Ris lower alkyl.

Alternatively, treatment of the 17-keto derivatives (VIII) and (VIIIa)with, for instance, lithium acetylideethylenediamine complex may becarried out to produce 17a-ethynyl-17B-hydroxy derivatives correspondingto Formulas IX and lXa, which may be acylated as with acetic anhydridein the presence of perchloric acid to form the corresponding17ot-ethynyl-17B-acetate derivatives.

Catalytic hydrogenation of either the 17a-ethynyl-17B- hydroxy or theI7a-ethynyl-17B-acetate compounds may be performed to produce after theuptake of one mole equivalent of hydrogen the corresponding 17a-vinylcounpounds corresponding to Formulas IX and IXa. Likewise, completesaturation of the side chain by hydrogenation produces the corresponding1 7a-ethyl compounds.

In order to prepare the desired acyl derivatives of the instantinvention, the respective primary or secondary hydroxy compounds may betreated with an acylating agent, such as an acidic anhydride or an acylhalide, in the presence of an organic base, such as pyridine.

The invention may be illustrated by the following examples:

EXAMPLE 1 A-norandnostane-Lone-Sflfifi,17fl-triol A mixture of 3.25 g.of A-nortesrtrosterone and 3.0 g.

of osmium tetroxide in 3 ml. of pyridine and 60 m1. of benzene isstirred at room temperature for forty-eight hours. The reaction mixtureis diluted with 100 ml. of dioxane and treated with hydrogen sulfide forfive minutes. The precipitate is filtered and the filtrate is evaporatedto dryness and crystallized from ethyl acetate to give A-norandrostane-2one-3{3,'5,8,17fl-t1riol EXAMPLE 2 3-oxa-A-norandrostane-58,17,8-diol-2-one A solution of 3.9 g. of periodic acid in 10 ml. ofwater is added to a solution of 1.93 g. of A-norandrostane-2-one3u,5a,17,8-triol in 10 ml. of pyridine and 80 ml. of methanol and thereaction mixture is left at room temperature for sixteen and one-halfhours. The reaction mixture is evaporated to near dryness, and theresidue diluted with Water and extracted three times with chloroform.The chloroform extracts are extracted three times with a saturatedsodium bicarbonate solution. The aqueous phase is acidified andextracted four times with ethyl acetate. The ethyl acetate extracts arewashed with 8% salt solution, dried over sodium sulfate, and evaporatedto dryness. Crystallization of the residue from ether-ethyl acetategives 1.14 g. of 3-oxa-A-norandrostane -5,,B,17fl-diol-2-one having amelting point of 183-184".

EXAMPLE 3 2,5 -seco-3,4-bisnor-andro Shane-5 ,8, 17 B-diol-2-oic acid Asolution of 60 mg. of 3oXa-A-norandrostane-5a,175- diol-2-one in 5 ml.of ethanol is stirred overnight with a solution of 45 mg. of sodiumborohydride in 1 ml. of Water. The reaction mixture is poured intowater, acidified, and extracted three times with ether. The etherextracts are washed with an 8% salt solution, dried over sodium sulfate,and evaporated to dryness. Crystallization of the residue frommethanol-ether gives 24 mg. of 2,5 seco 3,4 bisnoran-drostane5,3,17,6-diol 2 o ic acid having a melting point of 200-202".Recrystalliza tion from methanol-isopropyl ether gives the analyticalsample having melting point 203-204 [a] |32 (EtOH);

A5,; 3.03, 5.80, and 5.97;

Analysis.--Calcd. for C17H23O4 (296.39): C, 68.89; H, 9.52. Found: C,68.81; H, 9.54.

EXAMPLE 4 3 oxa-5a-A-norandFostane-Z-one-175-01 acetate W 5.65, and 5.30

max

Analysis.-Calcd. for C H O (320.41): C, 71.22; H, 8.81. Found: C, 71.41;H, 8.86.

EXAMPLE 5 2, 5 seco-3 ,4 bisnorandao stane-2, 5:5, 17 fl-triol Asolution of 300 mg. of 3- oxa-5a-A-nopandlrostaneone-171301 acetate in20 ml. of ether is added at room temperature to a stirred suspension of300 mg. of lithium aluminum hydride in ml. of ether over a period of tenminutes. The reaction mixture is refluxed for twenty-four hours, thentreated with water-saturated ether and dilute hydrochloric acid. Theether layer is separated and the max Analysis.--Calcd. for C H O(282.41): C, 72.30; H, 10.71. Found: C, 72.42; H, 10.57.

EXAMPLE 6 3-oxa-5a-A-norandrostane175-01 acetate (a) A mixture of 105mg. of 2,5-seco-3,4-bisnorandrostane-2,5 8,l7,8-triol and 140 mg. ofp-toluenesulfonyl chloride in 7 ml. of pyridine is left at roomtemperature for sixteen hours, then warmed on a steam bath for threehours. The reaction mixture is poured into ice-water and extracted threetimes with chloroform. The chloroform extracts are washed with aZN-hydrochloride acid solution, a saturated sodium bicarbonate solution,8% salt solution, dried over sodium sulfate and evaporated to dryness.Plate chromatography of the residue using neutral alumina (Activity V)as the adsorbent and chloroform as the developing solvent gives a majorband at about Rf 0.5, which is detectable by iodine vapor. Elution withethyl acetate gives 71 mg. of 3-oxa-5a-A-norandrostane-17fi-ol.

(b) The 3-oxa-5u-A-norandrostane-175-01 is acetylated by refluxing in 1ml. of acetic anhydride and 0.1 ml. of pyridine for forty-five minutes.The reaction mixture is poured into ice-water and extracted three timeswith ether. The extracts are washed with a saturated sodium bicarbonatesolution, 8% salt solution, dried over sodium sulfate, and evaporated todryness. The residue is chromatographed as described above using hexanecontaining 10% chloroform as the developing solvent. Elution with ethylacetate and crystallization from petroleum ether gives 33 mg. of3-oxa-5a-A-norandrostane-l7fl-ol acetate having a melting point of1l8l19. Recrystallization from petroleum ether gives the analyticalsample having melting point 118.5-1195"; [a] (ETOH);

TSi(CH3)4 9.19 (s., 19-Me), 9.18 (s., 18-Me), 7.97 (s., 17- acetate),6.95 (d., 4 cps., 11.7 cps., 5-H), 5.39 (m., 17-H).

Analysis.Calcd for C H O (306.43); C: 74.47; H: 9.87. Found: C: 74.46;H: 9.73.

EXAMPLE 7 3-oxa-5 a-A-norandrostane-17-one A solution of 200 mg. of3-oxa-5a-A-norandrostane-17B- 01 in 6 ml. of acetone is treated dropwisewith stirring with an excess of chromium trioxide-sulfuric acid. Thereaction mixture is stirred for four minutes and then two drops ofethanol are added. The acetone is decanted and the inorganic residuewashed with additional acetone. Evaporation of the combined acetonefractions gives 3- oxa-5a-A-norandrostane-17-one.

EXAMPLE 8 17a-methy1-3 -oxa-5a-A-norandrostane-17 3-01 max methylmagnesium bromide, there is obtained the respective 17 a-alkylsubstituted compound, i.e., 17a-ethyl-3-oxa- 5a-A-norandrostane-17,8-01,L-PTOPY1-3-OXfl-S a-A-norandrostane-17fi-ol, and17a-hexyl3-oxa-5u-A-norandrostane- -01.

EXAMPLE 9 2,5-seco-3,4-bisnorandrostane-2,5/3, l 7fl-triol-2,5, l7-

triacetate Following the procedure set forth in Example 6b butsubstituting equivalent amounts of 2,5-seco-3,4-bisnorandrostane2,5,43,17,8-trio1, for 3 oxa 5oz A androstane- 17,8-01, there isobtained 2,5-seco-3,4-bisnorandrostane-2, 5B,173-triol-2,5,l7-triacetate.

EXAMPLE 1O 3-oxa-5a-A-norandrostane-175-01 octanoate Following theprocedure of Example 6b but substituting an equivalent amount ofoctanoic anhydride for the acetic anhydride, there is obtained3-oxa-5ot-A-norandrostane-17B-ol octanoate.

EXAMPLE 11 17a-methyl-3-oxa-5a-A-norandrostane-17 8-01 dodecanoateFollowing the procedure of Example 6b but substituting equivalentamounts of 17a-methyl-3-oxa-5a-A-norandrostane-17B-ol for the3-oxa-5u-A-norandrostane-1718-01 and dodecanoic anhydride for the aceticanhydride, there is obtained 17a-methyl-3-oxa-5a-A-norandrostane-17,8-01dodecanoate.

EXAMPLE 12 2,5-seco-3,4-bisnorandrostane-2,5fl, l7fi-triol; 2,5-seco-3,4-bisnorandrostane-2,5a,17 8-triol A mixture of 500 mg. of3-oxa-A-norandrostame-5p, 17,8-diol-2-one and 750 mg. of lithiumaluminum hydride in 25 ml. of tetrahydrofuran is refluxed for one day.The reaction mixture is treated with Water and 2N hydrochloric acid andthe organic solvents evaporated. The aqueous phase is filtered and theprecipitate heated in methanol. The methanol solution is filtered andevaporated to dryness. The residue is crystallized frommethanol-isopropyl ether to give 2,5-seco-3,4-bisnorandrostane-2,513,17,8-triol. The mother liquor is a mixture of the 50cand Sis-01s.

EXAMPLE 13 3-oxa-5,B-A-norandrostane-17,8-01

The mother liquor from Example 12 is stirred for four hours at roomtemperature in 5 ml. of acetone containing 0.1 ml. of 70% perchloricacid. The reaction mixture is evaporated and the residue taken up inchloroform. The chloroform solution is washed with 8% salt solution,dried over sodium sulfate and evaporated. Plate chromatography of theresidue on neutral alumina (Activity V) using chloroform-hexane (2: 1)as the developing solvent gives a major band detectable with iodine.Elution with ethyl acetate and evaporation to dryness gives3-oxa-5fi-A-norandrostane-17fi-ol.

EXAMPLE 14 3 -oxa-5,6-A-norandrostane- 17,8-01 acetate Room temperatureacetylation of 3-oxa-5fi-A-norandrostane-17B-ol with acetic anhydride inpyridine gives 3-oxa- 5 3-A-norandrostane-175-01 acetate.

EXAMPLE 15 3-oxa-5B-A-norandrostane-17-one Following the procedure inExample 7, but substituting 3-oxa-5fl-A-norandrostane-176-01 for3-oxa-5a-A-norandros=tane17pol, there is obtained 3oxa-53-A-norandrostane- 17-one.

EXAMPLE 16 17m-ethynyl-3-oxa-5u-A-norandrostane-1713-01 A mixture of 707mg. of 3-oxa-5ot-A-norandrostane-17- one and 1 g. of lithiumacetylide-ethylenediamine complex in 25 ml. of benzene and 25 ml. oftetrahydrofuran is warmed at about 50 under nitrogen with stirring for21 hours. Water (20 ml.) is added and the reaction mixture is refluxedfor one hour, cooled and the organic layer separated. The aqueous phaseis extracted with chloro- 3 5 9.15 (3., 18-Me, 19-May) 7.45 (s,17a-ethynyl), 6.95 (d,d, 4 cps., 11.5 cps., Set-H) and 6.12 (d,d, 6cps., 9 cps., 2-CH Analysis.-Calcd. for C H O (288.41): C, 79.12; H,9.79. Found: C, 79.14; H, 9.82.

EXAMPLE 17 17a-vinyl-3-oxa-5m-A-norandrostane-17 8-01 A solution of 500mg. of 17u-ethynyl-3-oxa-5a-A-norandrostane-17fi-ol in 25 ml. of dioxaneis hydrogenated in the presence of 50 mg. of 5% Pd/C catalyst until onemole-equivalent of hydrogen is consumed. The catalyst is removed byfiltration and the filtrate evaporated to give17a-vinyl-3-oxa-5a-A-norandrostane-1713-01.

EXAMPLE 18 17a-ethyl-3-oxa-5a-A-norandrostane-175-01 A solution of 279mg. of 17a-ethynyl-3-oxa-5a-A-norandrostane-17fl-ol in 15 ml. of dioxaneis hydrogenated in the presence of 50 mg. of 5% Pd/C catalyst until theuptake of hydrogen ceased. The catalyst is removed by filtration and thefiltrate is evaporated. The residue is crystallized fromchloroform-isopropyl ether to give 144 mg. of17u-ethyl-3-oXa-5u-A-norandrostane-175-01, M.P. 161.5163.5.Recrystallization from ether gives the analytical sample; M.P.165.5167.5 [a] |3 (EtOH); AKBI 2.92 4;

9.16 (s., 18-Me) 9.11 (s, 19-Me), 9.03 (s, 17a-CH CH 6.94 (m, Set-H) and6.10 (d,d, 5.5 cps., 9 cps., 2-CH Analysis.Calcd. for C H O (292.45): C,78.03; H, 11.03. Found: C, 78.09; H, 10.86.

EXAMPLE 19 17a-ethynyl3-oxa-5B-A-norandrostane-17 8-01 Following theprocedure in Example 16, but substituting 3-oxa 513 Anorandrostane-17-one for 3-oxa-5u-A- norandrostane-17-one, there isobtained 17a-ethynyl-3- oxa-SB-Amorandrostane-17fl-ol.

EXAMPLE 20 17u-vinyl-3-oxa-5;3-A-norandrostane-17 8-01 Following theprocedure in Example 17, but substituting17a-ethynyl-3-oxa-5fi-A-norandrostane17,8-01 for 170:-

ethynyl 3 oxa-5u-A-norandrostane-175-01, there is obtained17a-viny1-3-oxa-5fl-A-norandrostane-1713-01.

10 EXAMPLE 21 17u-ethyl-3 -oxa-5fi-A-norandrostane-175-01 Following theprocedure in Example 18, but substitutingl7a-ethynyl-3-oxa-Sfi-A-norandrostane-17/3-ol for 1704-- ethynyl -3oXa-5a-A-norandrostane17,8-01, there is obtained17a-ethyl-3-oxa-5fi-A-norandrostane-1718-01.

What is claimed is:

1. A compound of the formula wherein each R and R' is hydrogen andtogether R and R is oxo (O); R" is selected from the group consisting ofhydroxy and acyloxy, wherein the acyl radical is of a straight chainsaturated hydrocarbon carboxylic acid of up to twelve carbon atoms; X isselected from the group consisting of hydrogen, lower alkyl, loweralkenyl and lower alkynyl; and together X and R" is oxo, H beingu-bonded when R and R is 0x0.

2. A compound of claim 1 having the name 3-OXa-5a-A-norandrostane-Ufi-ol.

3. A compound of claim 1 having the name 3-oxa-5fi-A-norandrostane-lm-ol.

4. A compound of claim 1 having the name 3-oxa-5a-A-norandrostane-l7fi-ol acetate.

5. A compound of claim 1 having the name S-OXa-Sfl-A-norandrostane-17fi-o1 acetate.

6. A compound of claim 1 having the name 3-oxa-5a-A-norandrostane-17-one.

7. A compound of claim 1 having the name 3-oxa-5p-A-norandrostane-17-one.

8. A compound of claim 1 having the name 17u-methyl-3-oxa-5a-A-norandrostane-1718-01.

9. A compound of claim 1 having the name 17oz-ethyl-3-oxa-5ct-A-norandrostane-1713-01.

10. A compound of claim 1 having the name 17u-vinyl-3-oxa-5u-A-norandrostane-17 3-01.

11. A compound of claim 1 having the name17u-ethynyl-3-oxa-5a-A-norandrostane-17 8-01.

12. A compound of claim 1 having the name 17amethyl-3-oXa-58-A-norandrostane-175-01.

13. A compound of claim 1 having the name 17a-ethyl-3-oxa-5fi-A-norandrostane-1713-01.

14. A compound of claim 1 having the name 17u-vinyl-3-oXa-5B-A-norandrostane-17fi-ol.

15. A compound of claim 1 having the name17u-ethynyl-3-oxa-5fi-A-norandrostane-175-01.

16. 3-oxa-5a-A-norandrostane-2-one-17fl-o1 acetate.

References Cited Pettit, G. R., Synthesis of Oxasteroids, May 18, 1961,pp. 4557-63.

ALEX MAZEL, Primary Examiner ANNE MARIE T. TIGHE, Assistant Examiner US.Cl. X.R.

mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,483,223 Dated December 9, 1969 Inventor) fievmour D. Levine andPatrick A. Diassi It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 5, line 36, "pyridene" should read -pyridine-- and in line 60,after "produce" insert and in line after "hydrogen" insert Column 7,line 22, "hydrochloride" should read hydrochloric Column 8, line 7O"drostanel7Bol, there is obtained 3oxa" should read drostane-l7fi-ol,there is obtained 3-oxa Column 10, line 21, (0-) should read (O=) SIGNEDKND SEALED JUN161970 mm In W J Awesnngflmw flomissiom or hm

